Hard tissues including bone and teeth in a human body include approximately 80% of inorganic material and water, and 20% of organic materials, and the organic materials consist of 80% of collagen protein, and 20% of non-collagen protein. These protein components contribute to maintaining generation, structural strength and elasticity of hard tissue, inducing attachment of hard tissue-forming cells such as osteoblast cell, and the like, and functioning as a matrix which orientates inorganic ion components configuring hard tissue components (Anselme, Osteoblast adhesion on biomaterials, Biomaterials, 21 (7): 667-81, 2000).
Various researches for developing human-derived proteins as medical biomaterials for substituting or replacing bio-functions have been conducted, and various bio-materials that mimic natural tissue have also been developed according to development of a biotechnological technique.
The bio-materials need to be biologically suitable, and are divided into three classes depending on the degree of contact with a human body. A first class includes materials that are not in contact directly with a human body or do not change fluid composition even though they are in contact with human, a second class includes materials that are in contact intermittently or in a short time such as within 24 hours, and a third class which is a transplant includes materials that are inserted into a human body to be in continuous contact with the tissue, in particular, the third class materials are required to guarantee complete stability with respect to a human body (regulations regarding approval, inspection, examination, etc., of a medical device by the Food and Drug Administration). These third class materials may be divided into bioinert materials that maintain a form and a shape without causing an immune response after transplantation according to biological reaction forms with surrounding tissues, bioactive materials that are directly bound to surrounding tissues to provide biological functions, and biodegradable materials that are slowly decomposed in body after transplantation and substituted with autologous generation tissue. In addition, biostability and biocompatibility need to be considered in the biomaterials. A representative method using natural tissue as the biomaterial is allograft. However, in accordance with recent development of molecular biology, protein engineering, and the like, it is possible to treat the natural tissue itself to be directly used, or to extract target tissue components (Medical polymer material, Korea Institute of Science and Technology Information).
A representative natural polymer used as the biomaterial is an extracellular protein, in particular, collagen, fibronectin, vitronectin, and the like, are representative examples. For example, peptide sequence consisting of arginine (R)-glycine (G)-aspartic acid (D) that induces cell adhesion included in collagen or fibronectin, and therefore, when RGD peptide is artificially arranged on a surface of the biomaterial, environment for inducing the surface of the material and the adhesion of the cell is provided to mimic function of the natural tissue by binding with surrounding cells (FIG. 1) (Grzesik et al., Bone Matrix RGD Glycoproteinsimmunolocalization and interaction with human primary osteoblastic bone cells in vitro, J Bone Miner Res, 9: 487-496, 1994).
Further, these collagen proteins are present in soft tissue such as skin dermis layers, mucosa layers, and the like, and these collagen proteins form bundles in subcutaneous tissue and bind to inorganic ions in body fluid components to maintain elasticity of the dermis and mucosal tissue and to function as a base matrix for the proliferation of cells and formation of soft tissue (Casser-Bette et al., Bone formation by osteoblast-like cells in a three dimensional cell culture, Calcif Tissue Int, 46: 46-56, 1990). Therefore, research into biomaterials made of apatite-containing inorganic materials or manufactured by coating inorganic materials on surfaces of polymers or proteins so as to be used as materials for restoration of bone tissue defect or subcutaneous tissue has been continuously conducted.
However, existing tissue regeneration technology in which apatite-containing inorganic materials or synthetic or natural polymers, in particular, collagen-derived proteins are applied alone has limited effects in view of a final biomechanical role of tissue, that is, complete restoration of biological functions.
An object of the biomaterial for tissue regeneration is to maintain biomechanical role of damaged tissue after transplantation, and accordingly, to restore morphological and physiological functions of tissue. Therefore, apatite transplant materials for being used as the biomaterial need to be directly usable, promote rapid tissue generation and revascularization in tissue, and maintain support and continuity of tissue, and not to cause an immune reaction, and the like, to thereby basically satisfy these conditions (Medical polymer material, Korea Institute of Science and Technology Information).
In the apatite-protein structure, even though the structure is swollen by body fluid, bone minerals included in the structure needs not to be separated to the outside of the structure in view of structural stability, unlike the existing simply mixed structure. When the apatite is not separated from the structure but stably contained in the structure, the apatite finally acts as a conductor which promotes stability when cells move. In addition, the protein structure containing apatite also needs to contribute to the above-described tissue generation capacity and revascularization in tissue. That is, the manufactured apatite-protein structure needs to provide conductivity in cell proliferation and tissue formation. However, these structures themselves function as a medium having bone conductivity; however, lack tissue inducing power for initial tissue formation that is essential to shorten a treatment period.
Researches into technology of using bioactive materials such as extracellular matrix proteins, tissue growth factors, or tissue formation proteins, together with tissue regeneration materials, in the structure so that the structure is mimicked to be close to tissue environment while overcoming the above-described disadvantages were conducted, and products such as INFUSE (containing BMP-2), GEM21S (containing PDGF), and the like, were developed (Anselme, Osteoblast Adhesion on Biomaterials, Biomaterials, 21 (7), 667-681, 2000). However, these proteins do not stably fix to the structure, and are instead discharged from the structure and degraded at the time of being exposed to blood of body, such that it is difficult to continuously maintain activity of tissue regeneration.
Accordingly, in order to overcome the above-described problems, a mimic having a structure and providing functions of conducting cell movement in the tissue at the time of filling biomaterials into damaged tissue while implementing a tissue environment, and finally inducing a regeneration function by protein or bioactive materials is required to be developed.
Therefore, the present inventors made an effort to solve the problems of the related art as described above, developed a tissue structure mimetic in which extracellular matrix protein and bone mineral component are organically bound to each other so as to have a composition that is similar to that of hard tissue constitution, found that the tissue structure mimetic is formable according to shapes of a transplant area as well as hard tissue to provide a high effect for tissue regeneration, and completed the present invention.